ABSTRACT While the lung has long been known to undergo extensive regeneration during adulthood, the particular stem cells involved in this process are only now being discovered. Recent studies have indicated that a subset of alveolar Type II cells, a known stem cell population of the alveoli, are preferentially activated to proliferate following different forms of injuries. Our preliminary data indicate that we have identified a novel stem cell population located in the periphery of the adult mouse lung. These cells constitute a subset of Type II cells and express SOX9, a transcription factor present in lung development but one whose expression had been previously thought to subside by adulthood. Our preliminary data show that Sox9-lineage labeled cells expand, generating new alveolar structures preferentially in the periphery of the lung lobes following partial left lobe pneumonectomy in mice. Moreover, both Sox9+ and Sox9 negative cells upregulate and re-express SOX9 in 3-dimensional organoid cultures, further suggesting that SOX9 functions to promote ?stemness? in alveolar cells. Given these findings, we hypothesize that Sox9+ cells are the primary alveolar stem cell, that they preferentially proliferate to repopulate the homeostatic and post-pneumonectomy lung parenchyma, that they are necessary for these processes, and that SOX9 enhances regenerative and differentiation potential of alveolar cells. We will address these questions using a combination of lineage tracing, cell-type specific ablation, ex vivo assays, and RNA- Sequencing approaches. Aim 1 will address the contribution of Sox9+ cells to both homeostasis and compensatory lung growth following pneumonectomy. Aim 2 will determine whether Sox9+ cells are essential for maintenance of alveolar homeostasis and injury repair. Aim 3 will address whether SOX9 expression can substantially influence the stemness of alveolar Type II cells. Collectively, answering these questions will help determine whether Sox9+ cells and/or SOX9 protein are viable therapeutic targets that will help accelerate lung repair following acute injury. !